Animal models of atherosclerosis have shown that oxidized lipoproteins and free radical molecules oxidize nitric oxide (NO) into biologically inert or toxic molecules, with the net effect of reduced NO bioactivity. In order to determine the mechanism of angiotensin converting enzyme (ACE) inhibitor-mediated mprovement in endothelium-dependent vasodilation in coronary artery disease (CAD), we administered quinapril 20-40 mg daily for 8 weeks to 9 men with CAD, with measures of brachial artery flow-mediated dilation (FMD) following forearm ischemia and serum NO2/NO3 on a 3-day nitrogen-free diet. We also measured endothelium- independent dilation after nitroglycerin (TNG). Data = mean +/- SD. On quinapril therapy, FMD increased to 10.8+/-2.2% from a baseline value of 2.4+/-0.4% (p<0.001): one week after therapy FMD declined to 6.7+/-2.5%. The response to nitroglycerin was similar at baseline (12.5+/-2.8%), on quinapril (14.1+/-3.4%), and one week off therapy (13.7+/-2.9%). Serum nitrogen oxide declined on quinapril therapy (46.0+/-13.3 microM) compared with baseline values (58.2+/-19.0 microM, p<0.02); one week off therapy levels had increased to 56.1+/-14.8 microM. Significant improvement in FMD following 8 weeks of quinapril therapy was accompanied by reduction in the luminal release of NO into the bloodstream. These data suggest that ACE inhibitors may reduce angiotensin II-induced oxidant stress within the vessel wall, with protection of NO from oxidation. Reduced NO degradation in turn may reduce the rate of NO synthesis required for vasomotor regulation. We conclude that ACE inhibitor therapy improves NO bioactivity with enhanced endothelium-dependent vasodilator responsiveness that is accomplished at a lower rate of NO synthesis.